UNIVERSIDADE FEDERAL DO RIO GRANDE DO NORTE

INSTITUTO DO CÉREBRO

Boletim de Publicações

maio a junho

Natal

2018

APRESENTAÇÃO

Este boletim é uma fonte de informação secundária destinada a promover o acesso e a

divulgação da produção científica dos pesquisadores do Instituto do Cérebro (ICe) da

Universidade Federal do Rio Grande do Norte (UFRN). Esta edição reuniu artigos publicados

entre os meses de maio a junho de 2018. Além de apresentar o título e o resumo dos

documentos, fornece um link de acesso ao texto completo, preferencialmente pelo Repositório

Institucional desta Universidade.

O ICe é Unidade Acadêmica Especializada que passou a integrar a estrutura

acadêmica e administrativa da UFRN em 29 de dezembro de 2010, por meio da resolução no

016/2010 do Conselho Universitário (CONSUNI). Essa Unidade é voltada para o

desenvolvimento da tríade ensino, pesquisa e extensão, com forte ação para a

internacionalização dos programas na área de Neurociências, abrangendo os Cursos de:

Pós-Graduação Stricto Sensu em Neurociências, em nível de Mestrado e Doutorado.

Bacharelado em Ciências e Tecnologia, com formação generalista no eixo de

Neurociências.

SUMÁRIO

ARTIGOS

Speech structure links theneural and socio-behavioural correlates of psychotic disorders ........ 5

Whole genome sequencing of the Pirarucu (Arapaima gigas) supports independent emergence

of major teleost clades ................................................................................................................ 6

OLMa2 cells bidirectionally modulate learning ......................................................................... 7

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a

randomized placebo-controlled trial ........................................................................................... 8

Cortisol modulation by ayahuasca in patients with treatment resistant depression and healthy

controls ....................................................................................................................................... 9

Direct reprogramming of adult human somatic stem cells into functional neurons using Sox2,

Ascl1 and Neurog2 ................................................................................................................... 10

Complex landscape of germline variants in brazilian patients with hereditary and early onset

breast cancer ............................................................................................................................. 11

Whole Organisms or Pure Compounds? Entourage Effect Versus Drug Specificity.......... 12

4

ARTIGOS

5

Mota NB, Oowise S, Balain V, Copelli M, Ribeiro S, Liddle P (2018). Speech structure links

the neural and socio-behavioural correlates of psychotic disorders. Progress in Neuro-

Psychopharmacology and Biological Psychiatry. doi: 10.1016/j.pnpbp.2018.07.007

Speech structure links theneural and socio-behavioural correlates of psychotic disorders

Abstract

Background: A longstanding notion in the concept of psychosis is the prominence of

loosened associative links in thought processes. Assessment of such subtle aspects of thought

disorders has proved to be a challenging task in clinical practice and to date no surrogate

markers exist that can reliably track the physiological effects of treatments that could reduce

thought disorders. Recently, automated speech graph analysis has emerged as a promising

means to reliably quantify structural speech disorganization. Methods: Using structural and

functional imaging, we investigated the neural basis and the functional relevance of the

structural connectedness of speech samples obtained from 56 patients with psychosis (22 with

bipolar disorder, 34 with schizophrenia). Speech structure was assessed by non-semantic

graph analysis. Results: We found a canonical correlation linking speech connectedness and

i) functional as well as developmentally relevant structural brain markers (degree centrality

from resting state functional imaging and cortical gyrification index) ii) psychometric

evaluation of thought disorder iii) aspects of cognitive performance (processing speed

deficits) and iv) functional outcome in patients. Of various clinical metrics, only speech

connectedness was correlated with biological markers. Speech connectedness filled the

dynamic range of responses better than psychometric measurements of thought disorder.

Conclusions: The results provide novel evidence that speech dysconnectivity could emerge

from neurodevelopmental deficits and associated dysconnectivity in psychosis.

Keywords: Disorganization. Bipolar disorder. Schizophrenia. Thought disorder. Gyrification.

Centrality. Graph theory

URI: https://repositorio.ufrn.br/jspui/handle/123456789/25588

6

Vialle RA et al. (2018). Whole genome sequencing of the Pirarucu (Arapaima gigas) supports

independent emergence of major teleost clades. Genome Biology and Evolution, evy130. doi:

https://doi.org/10.1093/gbe/evy130

Whole genome sequencing of the Pirarucu (Arapaima gigas) supports independent

emergence of major teleost clades

Abstract

The Pirarucu (Arapaima gigas) is one of the world's largest freshwater fishes and member of

the superorder Osteoglossomorpha (bonytongues), one of the oldest lineages of ray-finned

fishes. This species is an obligate air-breather found in the basin of the Amazon River with an

attractive potential for aquaculture. Its phylogenetic position among bony fishes makes the

Pirarucu a relevant subject for evolutionary studies of early teleost diversification. Here, we

present, for the first time, a draft genome version of the A. gigas genome, providing useful

information for further functional and evolutionary studies. The A. gigas genome was

assembled with 103 Gb raw reads sequenced in an Illumina platform. The final draft genome

assembly was approximately 661 Mb, with a contig N50 equal to 51.23 kb and scaffold N50

of 668 kb. Repeat sequences accounted for 21.69% of the whole genome, and a total of

24,655 protein-coding genes were predicted from the genome assembly, with an average of 9

exons per gene. Phylogenomic analysis based on 24 fish species supported the postulation that

Osteoglossomorpha and Elopomorpha (eels, tarpons and bonefishes) are sister groups, both

forming a sister lineage with respect to Clupeocephala (remaining teleosts). Divergence time

estimations suggested that Osteoglossomorpha and Elopomorpha lineages emerged

independently in a period of approximately 30 million years in the Jurassic. The draft genome

of A. gigas provides a valuable genetic resource for further investigations of evolutionary

studies and may also offer a valuable data for economic applications.

Keywords: Arapaima gigas. Pirarucu. Osteoglossomorpha. Teleostei. Genome

sequencing. Phylogenomics.

URI: https://repositorio.ufrn.br/jspui/handle/123456789/25587

7

Siwani S, França ASC, Mikulovic S, Reis A, Hilscher MM, Edwards SJ, Leão RN, Tort ABL,

Kullander K (2018). OLMa2 cells bidirectionally modulate learning. Neuron, 99, 1-9. doi:

https://doi.org/10.1016/j.neuron.2018.06.022

OLMa2 cells bidirectionally modulate learning

Abstract

Inhibitory interneurons participate in mnemonic processes. However, defined roles for

identified interneuron populations are scarce. A subpopulation of oriens lacunosum-

moleculare (OLM) interneurons genetically defined by the expression of the nicotinic

receptor α2 subunit has been shown to gate information carried by either the

temporoammonic pathway or Schaffer collaterals in vitro. Here we set out to determine

whether selective modulation of OLMα2 cells in the intermediate CA1 affects learning and

memory in vivo. Our data show that intermediate OLMα2 cells can either enhance (upon their

inhibition) or impair (upon their activation) object memory encoding in freely moving mice,

thus exerting bidirectional control. Moreover, we find that OLMα2 cell activation inhibits

fear-related memories and that OLMα2 cells respond differently to nicotine in the

dorsoventral axis. These results suggest that intermediate OLMα2 cells are an important

component in the CA1 microcircuit regulating learning and memory processes.

Keywords: OLM cells. Object recognition. Passive inhibitory avoidance. Memory.

URI: https://repositorio.ufrn.br/jspui/handle/123456789/25586

8

Palhano-Fontes F et al. (2018) Rapid antidepressant effects of the psychedelic ayahuasca in

treatment-resistant depression: a randomized placebo-controlled trial. Psychological

Medicine, 1-9. doi: 10.1017/S0033291718001356

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant

depression: a randomized placebo-controlled trial

Abstract

Background: Recent open-label trials show that psychedelics, such as ayahuasca, hold

promise as fast-onset antidepressants in treatment-resistant depression. Methods: To test the

antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized

placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a

single dose of either ayahuasca or placebo. We assessed changes in depression severity with

the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression

Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing. Results: We

observed significant antidepressant effects of ayahuasca when compared with placebo at all-

time points. MADRS scores were significantly lower in the ayahuasca group compared with

placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes

increased from D1 to D7 (D1: Cohen's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 1.49).

Response rates were high for both groups at D1 and D2, and significantly higher in the

ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward

significance at D7 (36% v. 7%, p = 0.054). Conclusions: To our knowledge, this is the first

controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this

study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed

within an appropriate setting, to help treat depression. This study is registered at

http://clinicaltrials.gov (NCT02914769).

Keywords: Ayahuasca. Depression. HRS. MEQ. Psychedelics. Randomized Controlled Trial

(RCT).

URI: https://repositorio.ufrn.br/jspui/handle/123456789/25439

9

Galvão ACM, Almeida RN, Silva EAS, Freire FAM, Palhano-Fontes F, Onias H, Arcoverde

E, Maia-de-Oliveira JP, Araújo DB, Lobão-Soares B, Galvão-Coelho NL (2018). Cortisol

modulation by ayahuasca in patients with treatment resistant depression and healthy controls.

Front. Psychiatry, 9:185. doi: 10.3389/fpsyt.2018.00185

Cortisol modulation by ayahuasca in patients with treatment resistant depression and

healthy controls

Abstract

Major depression is a highly prevalent mood disorder, affecting about 350 million people, and

around 30% of the patients are resistant to currently available antidepressant medications.

Recent evidence from a randomized controlled trial (RCT) supports the rapid antidepressant

effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study

was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol

response, in the same group of treatment-resistant patients (MD) and in healthy volunteers

(C). Subjects received a single dose of ayahuasca or placebo (dosing session), and both

plasma and awakening salivary cortisol response were measured at baseline (before dosing

session) and 48 h after the dosing session. Baseline assessment (D0) showed blunted

awakening salivary cortisol response and hypocortisolemia in patients, with respect to healthy

controls. Salivary cortisol was also measured during dosing session, and we observed higher

increases for both C and MD that ingested ayahuasca than placebo. After 48 h from the dosing

session with ayahuasca, patients' awakening salivary cortisol response is similar to the ones

detected in controls. No significant changes in plasma cortisol levels were observed 48 h after

the sessions. Therefore, these findings point to new evidence on the modulation of salivary

cortisol levels as a result of an ayahuasca session, both in healthy and depressive volunteers.

Considering that cortisol acts in regulation of distinct physiological pathways, emotional and

cognitive processes, it is assumed to be critically involved to the etiology of depression and its

regulation seems to be important for the treatment and remission of major depression,

ayahuasca use as antidepressant should be further investigated. Moreover, this study

highlights the importance of psychedelics in the treatment of human mental disorders.

Keywords: Awakening salivary cortisol. Ayahuasca. Hypocortisolemia. Plasma cortisol.

Treatment-resistant depression.

URI: https://repositorio.ufrn.br/jspui/handle/123456789/25440

10

Araújo JAM, Hilscher MM, Marques-Coelho D, Golbert DCF, Cornelio DA, Batistuzzo de

Medeiros SR, Leão RN, Costa MR (2018). Direct reprogramming of adult human somatic

stem cells into functional neurons using Sox2, Ascl1 and Neurog2. Front. Cell. Neurosci.,

12:155. doi: 10.3389/fncel.2018.00155

Direct reprogramming of adult human somatic stem cells into functional neurons

using Sox2, Ascl1 and Neurog2

Abstract

Reprogramming of somatic cells into induced pluripotent stem cells (iPS) or directly into cells

from a different lineage, including neurons, has revolutionized research in regenerative

medicine in recent years. Mesenchymal stem cells are good candidates for lineage

reprogramming and autologous transplantation, since they can be easily isolated from

accessible sources in adult humans, such as bone marrow and dental tissues. Here, we

demonstrate that expression of the transcription factors (TFs) SRY (sex determining region

Y)-box 2 (Sox2), Mammalian achaete-scute homolog 1 (Ascl1), or Neurogenin 2 (Neurog2) is

sufficient for reprogramming human umbilical cord mesenchymal stem cells (hUCMSC) into

induced neurons (iNs). Furthermore, the combination of Sox2/Ascl1 or Sox2/Neurog2 is

sufficient to reprogram up to 50% of transfected hUCMSCs into iNs showing electrical

properties of mature neurons and establishing synaptic contacts with co-culture primary

neurons. Finally, we show evidence supporting the notion that different combinations of TFs

(Sox2/Ascl1 and Sox2/Neurog2) may induce multiple and overlapping neuronal phenotypes

in lineage-reprogrammed iNs, suggesting that neuronal fate is determined by a combination of

signals involving the TFs used for reprogramming but also the internal state of the converted

cell. Altogether, the data presented here contribute to the advancement of techniques aiming

at obtaining specific neuronal phenotypes from lineage-converted human somatic cells to treat

neurological disorders.

Keywords: Induced neurons. Lineage reprogramming. Human mesenchymal stem cells.

Umbilical cord. Proneural genes.

URI: https://repositorio.ufrn.br/jspui/handle/123456789/25457

11

Torrezan GT, Almeida FGSR, Figueiredo MCP, Barros BDF, Paula CAA, Valieris R, Souza

JES, Ramalho RF, Silva FCC, Ferreira EN, Nóbrega AF, Felicio PS, Achatz MI, Souza SJ,

Palmero EI, Carraro DM (2018). Complex landscape of germline variants in brazilian patients

with hereditary and early onset breast cancer. Front. Genet. 9:161. doi:

10.3389/fgene.2018.00161

Complex landscape of germline variants in brazilian patients with hereditary and early

onset breast cancer

Abstract

Pathogenic variants in known breast cancer (BC) predisposing genes explain only about 30%

of Hereditary Breast Cancer (HBC) cases, whereas the underlying genetic factors for most

families remain unknown. Here, we used whole-exome sequencing (WES) to identify genetic

variants associated to HBC in 17 patients of Brazil with familial BC and negative for causal

variants in major BC risk genes (BRCA1/2, TP53, and CHEK2 c.1100delC). First, we

searched for rare variants in 27 known HBC genes and identified two patients harboring

truncating pathogenic variants in ATM and BARD1. For the remaining 15 negative patients,

we found a substantial vast number of rare genetic variants. Thus, for selecting the most

promising variants we used functional-based variant prioritization, followed by NGS

validation, analysis in a control group, cosegregation analysis in one family and comparison

with previous WES studies, shrinking our list to 23 novel BC candidate genes, which were

evaluated in an independent cohort of 42 high-risk BC patients. Rare and possibly damaging

variants were identified in 12 candidate genes in this cohort, including variants in DNA repair

genes (ERCC1 and SXL4) and other cancer-related genes (NOTCH2, ERBB2, MST1R,

and RAF1). Overall, this is the first WES study applied for identifying novel genes associated

to HBC in Brazilian patients, in which we provide a set of putative BC predisposing genes.

We also underpin the value of using WES for assessing the complex landscape of HBC

susceptibility, especially in less characterized populations.

Keywords: Cancer predisposition genes. Hereditary breast cancer. Whole-exome sequencing.

Germline pathogenic variants. Cancer susceptibility. DNA repair genes.

URI: https://repositorio.ufrn.br/jspui/handle/123456789/25458

12

Ribeiro S (2018). Whole organisms or pure compounds? entourage effect versus drug

specificity. In: Labate B, Cavnar C (Eds), Plant medicines, healing and psychedelic

science (pp. 133-149). New York: Springer.

Whole Organisms or Pure Compounds? Entourage Effect Versus Drug Specificity

Abstract

As the therapeutic use of sacred plants and fungi becomes increasingly accepted by Western

medicine, a tug of war has been taking place between those who advocate the traditional

consumption of whole organisms and those who defend exclusively the utilization of purified

compounds. The attempt to reduce organisms to single active principles is challenged by the

sheer complexity of traditional medicine. Ayahuasca, for example, is a concoction of at least

two plant species containing multiple psychoactive substances with complex interactions.

Similarly, cannabis contains dozens of psychoactive substances whose specific combinations

in different strains correspond to different types of therapeutic and cognitive effects. The

“entourage effect” refers to the synergistic effects of the multiple compounds present in whole

organisms, which may potentiate clinical efficacy while attenuating side effects. In opposition

to this view, mainstream pharmacology is adamant about the need to use purified substances,

presumably more specific and safe. In this chapter, I will review the evidence on both sides to

discuss the scientific, economic, and political implications of this controversy. The evidence

indicates that it is time to embrace the therapeutic complexity of psychedelics.

URI: https://link.springer.com/chapter/10.1007%2F978-3-319-76720-8_8#citeas